Reactive Oxygen Species Regulate Macrophage Scavenger Receptor Type I, but Not Type II, in the Human Monocytic Cell Line THP-1
- The William Harvey Research Institute, St. Bartholomew’s Hospital, Medical College, Charterhouse Square, London EC1M 6BQ, United Kingdom
Abstract
The uptake of modified low density lipoprotein via the macrophage scavenger receptor (MSR) results in the formation of lipid-laden foam cells during atherosclerosis. Because increased oxidative stress has been implicated in the pathogenesis of atherosclerosis, the role of reactive oxygen species on the activity and expression of MSR was investigated. The uptake of acetylated low density lipoprotein and the levels of MSR-I mRNA were inhibited by treatment with the oxygen radical scavengers 2,2,6,6-tetramethylpiperidine-N-oxyl, dimethylthiourea or sodium benzoate, or the iron chelator deferoxamine. Dimethylthiourea or benzoate also decreased the levels of MSR-I mRNA in the presence of the transcription inhibitor actinomycin D. These results indicate that hydroxyl radicals produced from superoxide anions and hydrogen peroxide in the presence of free iron, contribute to an increased MSR activity by stabilizing MSR-I mRNA. Several sources of reactive oxygen species are involved as inhibition of MSR activity and levels of MSR-I mRNA occurred in the presence of rotenone, a mitochondrial complex I inhibitor, or acetovanillone, a NADPH oxidase inhibitor. The (oxidative) stress responsive nuclear factor κB is not involved as inhibitors of its activation remained without significant inhibition. In contrast to MSR-I, the levels of MSR-II mRNA, which is formed by alternative splicing of the same gene transcript, were largely unaffected by the inhibitors of reactive oxygen species formation and activity. The present results suggest that oxidant stress contributes to an increased activity of MSR by stabilizing MSR-I mRNA.
Footnotes
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Send reprint requests to: Dr. Sjef J. de Kimpe, Department of Pharmacology, Faculty of Pharmacy, Utrecht University, PO Box 80.082, 3508 TB Utrecht, The Netherlands. E-mail:s.j.dekimpe{at}far.ruu.nl
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This work was supported by a fellowship from the Niels Stensen Foundation (the Netherlands) and the ONO Pharmaceutical company (Japan). S.J.D.K. receives a fellowship from the Netherlands Heart Foundation.
- Abbreviations:
- MSR
- macrophage scavenger receptor
- LDL
- low density lipoprotein
- AcLDL
- acetylated low density lipoprotein
- ROS
- reactive oxygen species
- TEMPO
- 2,2,6,6-tetramethylpiperidine-N-oxyl
- DMTU
- dimethylthiourea
- MTT
- 3-[4,4-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
- DiI
- 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate
- PDTC
- pyrrolidine dithiocarbamate
- AP-1 activator protein-1
- PMA, phorbol-12-myristate-13-acetate
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- LPS
- lipopolysaccharide
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- Received August 22, 1997.
- Accepted February 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
